Diabetic retinopathy is the leading cause of blindness in the US adult population. To develop, effective approaches to prevent this disease, there is a crucial need for a better understanding of the mechanisms of diabetes-induced retinal damage. We have recently found that glial Muller cells mount an acute-phase response in diabetes, which is accompanied by retinal induction of the inflammatory cytokine interleukin 1[unreadable] (IL-1[unreadable]). In this project, we intend to investigate the hypothesis that IL-1[unreadable] upregulation contributes to the glial and vascular abnormalities of the diabetic retina. The specific aims are: 1. To identify the cell type/s that upregulate IL-1[unreadable] and characterize the IL-1[unreadable] system in the diabetic retina. The retinal cell type/s expressing IL-1[unreadable] in diabetes will be identified by in situ hybridization and immunohistochemistry. To investigate the effect of diabetes on the IL-1[unreadable] system, we will study the retinal expression and cellular distribution of the two IL-1[unreadable] endogenous inhibitors - decoy receptor IL-1RII and receptor antagonist IL-1ra - and of the two components of the IL-1[unreadable] signaling receptor - IL-1RI and IL-1RAcP. 2. To determine the mechanisms and consequences of IL-1[unreadable] upregulation in retinal cells. We will perform in vitro studies to determine whether high glucose upregulates IL-1[unreadable] in cell culture models. We will then investigate whether IL-1[unreadable] is sufficient to mimic the effect of diabetes on Muller cells, and the interaction of IL-1[unreadable] with other diabetes-induced factors. 3. To determine whether inhibition of IL-1[unreadable] activity can prevent the development of diabetic retinopathy. As conclusive evidence for a role of IL-1[unreadable] in diabetic retinopathy, we will evaluate the effect of retinal overexpression of IL-1ra in preventing retinal abnormalities in diabetic rats. Identifying IL-1[unreadable] as a mediator of diabetes-induced retinal damage would open new avenues for the prevention of retinopathy. Recombinant IL-1ra or other anti-IL-1[unreadable] drugs could become powerful tools to prevent retinopathy - with possible applications to other diabetic complications with an inflammatory component such as atherosclerosis.